Aliphatic amino alcohols and medicinal preparations thereof



Patented Dec. 28, 1948 .ALIPHATIG. Ammo ALCOHQLSI. AND.MEDIC1- I PREPARATIONS THEREOF 2.. F. Givens 'llast Orange; and Riobert Herbst, Short N. .L, ansi'gnorsato. El. Bilhuber, Inc., Orange, N. J n corporation of New Jersey Nb Brawingpplication September 25, r945, Serial No. erase-a 4 Claims. 1

Our irtvernionv relates to new and, therapeuti cally useful aliphatic alcohols and medioinal preparations. thereof, .andmore particularly 70.43118 aminaalcoholshaving the following structural formula:

and to medicinal preparations containing the same as an active therapeutic ingredient, wherein R may be hydrogen. or :am ailkyl radical selected from the group one to. five. carbon atoms in a straight, or. branched chain. or an.

alkenyl radical or an .aralykl. radical. .or a cycloalkyl radical.

The aforesaid. ammo alcohols, 01 our invention have been found to be particularly valuable as therapeutic agents. They are effective pressor agentscausing elevation of the: blood pressure and are characterized especially by their stimulating action upon the heart. Their efiectiveness and therapeutic usefulness is further enhanced by an unusually low toxicity which sharply diiTerentiates them from the commonly employed pressor drugs. The, physiological elf-.ects of these new agents are evidenced upon. parenteral, oral or topical application.

These new amino alcohols may be suitably prepared as .iollows: When It is hydrogen, by the catalytichydrogenation of the oxime of. the corresponding. ketoalcohol; or when R is .a group other than hydrogen, by condensingthe proper lretoalcohol with. the appropriate. primary amine and reducing or partially reducing the resulting imino compomlxd or by additionof. the elements of water to the doublebond of theappropriate unsaturated secondary amine as illustrated by the examples cited below.

These. new amino, alcohols are colorless liquids of characteristic faint odor exhibiting varying degrees of viscosity. They generally exhibit solubili'tyin water and the common organic. solvents. Water-soluble salts with both organic and inorganic acids are; readily formed and the: aqueous solutions of these salts are particularly useful in: the therapeutic application of the amino alcohols. It may be noted that the amino alcohols described by the above formula contain within their structure a. single asymmetric carbon atom and that they are therefore resolvable into their optically active forms by suitable chemical methods.

The following examples are cited as illustrations of the procedures employed in the preparaticnaofwvarions. specific amino alcohols embraced by the general structural formula given above-:-

EXAMPLE I. .Z-amz'nO-G-methyZ-(i-hydroxy heptane One-tenth mole of G-methyl-G-hydroxy heptanone-2 oxime is dissolved in cc. of water and the solution treated with 0.1 mole of hydrochloric acidand 0.4 g of. platinum oxide catalyst,

The oxime is hydrogenated: at room temperature by agitating in an atmosphere of hydrogen atuan initial pressure of 50 lbs. per square inch. Upon complete reduction of the oxime, the catalyst is removed by filtration. The product is separated from the aqueous solution after neutralization of. the acid by the addition of inorganic salts and extraction with ether. Upon fractionation of the ether solution, 2-'amino-'6-methyl-6-hydl'oxy heptane is obtained as a colorless liquid" boiling at 92-93 at approximately 7 mm. of

mercury pressure.

H EXAMPLE II 2-methylamino-6-methyl -6-hydro.1:y heptane fine part oi. Z-methylamino-G-methyl heptene- 5is mixed with two parts of water and the mixture made :d-i-stinctly acid by the addition of mineral; acids. whereupon, the unsaturated amine dissolves: completely :The resulting sulutionl isv heated under reflux for half an hour, cooled to room temperature and treated with sufficient.

caustic soda to make the mixture strongly alkaline. The product separates. .as an oil which is easily removed by extraction. Upon distillation of the oil z methylamino-fi methyl fi hydroxy heptane is obtained as a colorless, viscous liquid boiling at 101-l03 C. at approximately 9 mm. of mercury pressure.

Exams-LE III zmflwcminoefi-methylebt-hydromu heptane llafilamolcl of G-methylz-fi-hydroxy heptanone-2- and .Qfi5moleof ally] amine are caused to react 7 EXAMPLE IV 2-ethyZamino-6-methyl-6-hydi'oxy heptane 0.5 mole of fi-methyl-fi-hydroxy -heptanone-2- and 0.55 mole of ethylamine are caused to react: mixture of 200 cc. of alcohol by dissolving in a and 300 cc. of water and reducing the resulting;

imino compound with 1.5 moles of activated aluminum. Upon completion of thereactiomgthe product is separated by extraction with ether.

Upon distillation of the ether solution, 2-ethylamino-G-methyl-6-hydroxy heptane is obtained? as a colorless liquid boiling at '102- -104 C; at

approximately 9 mm. of mercury pressure.

By application of the methods 'described in .total volume of 1955 cc.

EXAMPLEVII Solution of Z-methylamino-fi-methyl-fi-hydromy heptane hydrochloride One mole of 2emethylaminofi methyl-fi-hydroxy heptane and 1 moleof hydrochloric acid are dissolved in sufi'icient distilled water to make a This gives a 10% solution of 2 methylamino- 6 -methyl- 6 -hydroxy heptane hydrochloride which is used orally or placed in ampules and after sterilization by heai irlg under pressure for 30 minutes, is used parent erally. l

EXAMPLE VIII Solution of 2-methylaminofi-methyl-mhydrory the above examples to the appropriate oxime or to the proper unsaturated secondary amine or to mixtures of the appropriate primary amine and 6-methyl-6-hydroxy heptanone-2, the following new amino alcohols of this group have been The following examples are illustrative of the preparation of salts of the above compounds, and also of the compounding of medicinal agents containing these salts as active therapeutic ingredients of the character above stated:

EXAMPLE V 2-methylamino-6-methyl-6-hydroa:yheptane Y mucate I 2 moles of Z-methylamino-G-methyl-G-hydroxy heptane and 1 mole of mucic acid are mixed in' twice their weight of absolute methanol and the mixture warmed on a Water bath until solution results. Upon cooling, the Z-methylamino-G methyl-G-hydroxy heptane mucate crystallizes. M. P. 161-162 C.

EXAMPLE VI Preparation of tablets of Z-methylamino-G- 5 methyl-G -hydroxy heptane mucate One-half kilogram of 2-methylamino-6-methyl- G-hydroxy heptane mucate is intimately mixed with 0.8 kilogram of milk sugar and granulated with 70% isopropyl alcohol. After drying, the granulation may be pressed into tablets of suitable size and shape for therapeutic use, for example, to contain 130 mgm. (2 grs.) of the'salt which is equivalent to approximately 78 mgm. (l grs.) of

the free base.

heptane sulfate One mole of 2 methylamino- 6 -methyl- 6 hydroxy heptane and 0.5 mole of sulfuric acid are dissolved insuificientdistilled water to give a total volume of 2080 cc. 'This' results in a 10% solution of 2- methylamino-'6 -methyl-6-hydroxy heptane sulfate which s used orally or after described" in Example Q proper sterilization as is used parenterally.

EXAMPLE IX 100 grams of 2 methylamino-fi -methyl- 6 hydroxy heptane is dissolved-.in. sufficient 20% alcohol to make 1000 cc. This gives a solution which contains 0.1 gm. percc. and is suitable for oral administration. I V

EXAMPLE X grams of 2'- methylamino-S I hydroxy heptane is dissolved in suificient vegetableoil, such as peanut 'oil, to make'1000 cc.- This gives a solution which contains 0.1 gm. of the base in one cc. and is suitable for oral use or topical application.

We claim:

"1.- The therapeutically useru amino alcohols or the formula mg -wmiew a I "H-N-R 'on 4 Wherein R is a radical selected'irom the groi ms consisting of hydrogen; alkyl radicals havin'g from one to five carbon atoms, lower alknyl.

cycloalkyl and aralkyl radicals.

' 2. The therapeutically useful amino alcohol, 2-

methylamino-6-methyl-6-hydroxy heptane.

3. The therapeutically useiul amino alcohol ,"l2

amino- 6 methyl-6-hydroxy heptane.

4. The therapeutically useful am no alcohol, 2

ethylamino-o methyl-fi-hydroxy heptane;

REFERENCES C ITED The following" references are offref'c ordd file of this patent; f

Campbell et .al. J. Amer; Chem.- Smog-6 0 1372;

Rohrmann et al. JrAmer; chem; soc; 6611516 HORACE T. F. Givens, i ROBERT EBB 

